The voltage-gated calcium channels consist of an al subunit and auxiliary subunits α2δ, β, and γ. The α2δ subunit can regulate the density and voltage-dependent kinetics of the calcium channels (Felix et al., (1997) J. Neuroscience 17: 6884-6891; Klugbauer et al., (1999) J. Neuroscience 19:684-691; Hobom et al., (2000) Eur. J. Neuroscience 12: 1217-1226; and Qin et al., (2002) Mol. Pharmacol. 62:485-496). It has been demonstrated that compounds having a high affinity for the voltage-dependent calcium channel subunit α2δ, such as pregabalin and gabapentin, may be effective in the treatment of pain. In mammals, the α2δ subunit has four subtypes, each encoded by a different gene. α2δ subtype 1 and subtype 2 show a high affinity for pregabalin, while α2δ subtype 3 and subtype 4 do not have a significant binding capacity to a drug.
However, for gabapentin, the proportion of patients with diabetic peripheral neuropathy whose pain is relieved to a great extent by using gabapentin is approximately 60% (Acta Neurol. Scand. 101:359-371, 2000), while for pregabalin, although it is better tolerated than gabapentin, it is less safe and may be abused or induce drug dependence in patients (Am J Health Syst Pharm. 2007; 64(14): 1475-1482).
In view of the limitations of gabapentin and pregabalin, there is a need for developing new compounds having better efficacy.